CN1131390A - Plaster containing (E)-2-(P-fluorophenethyl)-3-fluoroallylamine for treatment of alzheimer's disease - Google Patents
Plaster containing (E)-2-(P-fluorophenethyl)-3-fluoroallylamine for treatment of alzheimer's disease Download PDFInfo
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- CN1131390A CN1131390A CN94193473A CN94193473A CN1131390A CN 1131390 A CN1131390 A CN 1131390A CN 94193473 A CN94193473 A CN 94193473A CN 94193473 A CN94193473 A CN 94193473A CN 1131390 A CN1131390 A CN 1131390A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The present invention relates to a method of treatment for Alzheimer's disease in a patient in need thereof comprising transdermally administering to said patient a therapeutically effective amount of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof. Also provided is a transdermal device for administration of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine or a pharmaceutically acceptable salt thereof.
Description
A compounds that is called as monoamine oxidase, MAO (MAO) inhibitor is used for the treatment of depression for a long time.MAO is the enzyme that plays an important role in the metabolism of naturally occurring monoamine is regulated.MAO is by the biodegradation of oxidation Deamination catalysis monoamines.These physiologically active monoaminess that are known as the MAO substrate have: (a) so-called " neurotransmission " monoamine, as catecholamines (dopamine for example, epinephrine and noradrenaline) and the indyl amine is (for example, tryptamines and serotonine), (b) so-called " spike " amine (O-tyramine for example, phenethylamine, far away-the N-.alpha.-Methylhistamine) and (C) tyramine.
Biochemistry and pharmaceutical research show that the MAO enzyme (MAO-A) exists with " MAO Type B " two kinds of forms (MAO-B) to be called as " MAO A type ".The difference of two kinds of forms is their distributions in the organ in vivo, and its Substratspezifitaet and they are to the sensitivity of inhibitor.Usually, MAO-A is oxidation so-called " neurotransmission " monoamines (epinephrine, noradrenaline and serotonine) optionally, and optionally oxidation of MAO-B " spike " monoamine (O-tyramine, phenethylamine and far away-N-.alpha.-Methylhistamine.MAO-A and MAO-B be oxidation tyramine, tryptamines and dopamine.Yet for the people, dopamine has been shown as the preferred substrate of MAO-B.MAO-A and MAO-B also at it to different aspect the sensitivity that suppresses, thereby it is different and optionally suppressed to look the relative concentration of the chemical constitution of inhibitor and/or inhibitor and enzyme." selectivity " that can observe the MAO inhibitor raises, because inhibitor has the affinity bigger than another kind to a kind of enzyme of form.Thereby inhibitor will depend on dosage to the selectivity of MAO-A or MAO-B, and when the concentration of inhibitor increased, selectivity had just been lost.For example, L-N, alpha-alpha-dimethyl-N-2-propinyl phenethylamine, 3 is the selective depressant of MAO-B in vivo when low dosage, but when dosage increases, becomes the non-selective inhibitor of MAO-A and MAO-B.
Show on evidence that now presenile dementia patient has the brain MAO-B activity higher than the old man of health.Known monoamines is playing crucial effect with memory with in the mental process of learning to be associated, show that also presenile dementia patient has the activity by monoamines such as dopamine, norepinephrine and the reduction of the different neurotransmission system of serotonine mediation.At last, MAO-B inhibitor L-N, alpha-alpha-dimethyl-N-2-propinyl phenethylamine appear as an effective therapeutic agent to the presenile dementia patient at present.[seeing Mangoni etc., Eur.Neurol.31,100 (1991)].
(to fluorobenzene ethyl-3-fluoroallylamine is a known selectivity MAO-B inhibitor to chemical compound (E)-2-, has the activity as the Mirapexin agent.
The present invention provides a kind of method for the treatment of presenile dementia for the patient who needs, and comprises (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt to said patient's administering therapeutic effective dose.The plaster of using (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt also is provided.
Chemical compound (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine is disclosed in the U.S. patent No. prevailingly and announced on June 12nd, 4,454,158,1984, is a kind of MAO-B inhibitor.This full patent texts is hereby incorporated by reference.Chemical compound (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine specifically is disclosed in the European patent application publication No. 0 295 604, and December disclosed on the 21st in 1988.
The pharmaceutically acceptable salt of chemical compound (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine is so organic and inorganic salts, and they are nontoxic and biopotency is arranged.For example, following salt is pharmaceutically acceptable: hydrochloric acid, hydrobromic acid, sulfonic acid, sulphuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, 4,4 ＇-di-2-ethylhexylphosphine oxide [3-hydroxyl-2-naphthoic acid], succinic acid, methanesulfonic acid, acetic acid, propanoic acid, tartaric acid, citric acid, lactic acid, malic acid, Alpha-hydroxy phenylacetic acid, cinnamic acid, Palmic acid, itaconic acid and benzene sulfonate.
Usually, (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine can be known by this specialty and the technology understood, as US-4,454,158 (being published on June 12nd, 1984), and the prepared described in the EP-0 295 604 (1988 on December 21, open).
Usually, (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine can by wherein to the diester of fluorophenyl ethyl butyric acid in known manner, the first step handles diester with highly basic and produces corresponding carbanion, carbanion contacts with suitable halogenated methylation agent and by the prepared of difluoromethylization then.Highly basic must be non-nucleophilicity and have enough intensity that proton is partly sloughed from the methine adjacent to the hydroxyl of starting ester.Suitable alkali is that this specialty is known, as disclosing among the EP-0 295 604 (December disclosed on the 21st in 1988).
After the difluoromethylization, preferably optionally remove in the ester group one by acidolysis.In order to reach selective splitting, preferably have a kind of mixing diester, (for example an ester group has the tert-butyl group to the easy cracking of one of them ester group, benzyl, diphenyl methyl or trityl group) and another has straight chained alkyl (for example methyl, ethyl, propyl group or normal-butyl).
Easy cracked ester group can by with organic or inorganic acid, be with or without solubilizer, with about 0 ° to about 25 ℃ temperature range, about 1 to 10 hour of response time handled and optionally hydrolysis.Room temperature is preferred.It is not crucial that selection is used for the acid of hydrolysis, just selects the acid that can remove at an easy rate after the hydrolysis stage.Trifluoroacetic acid is preferred, because its low boiling is removed it easily from hydrolyzate.When an ester group has benzyl, diphenyl methyl or trityl group and another is that straight chain C is arranged
1-C
4During alkyl, easy cracked ester group also can pass through the optionally cracking of quilt with the common process catalytic hydrogenolysis of blended diester: for example, (for example, Pd/C) existence was at room temperature handled 1 to 48 hour down at catalyst in nitrogen atmosphere.As conspicuous, can select ester group with by two groups of acidolysis or catalytic hydrogenolysis cracking simultaneously to skilled professional and technical personnel.
And then selective hydrolysis, the monoesters of difluoromethylization is by being converted into its acrylate with alkali treatment.React available moisture or nonaqueous solvent,, or carry out with weak base such as triethylamine or sodium carbonate with highly basic such as sodium hydroxide etc.For highly basic, thus must be carefully to avoid using excessive alkali to prevent the interaction of two keys.The selection of alkali, reaction dissolvent and reaction condition is conspicuous to skilled professional and technical personnel.A preferred technology is with the sodium hydrate aqueous solution among the THF under the room temperature.Usually, 0 ° to 25 ℃ of temperature range and 15 minutes to 2 hours response time can use.
Acrylate is reduced the generation 1-propenol-3.This transform used Reducing agent can be this specialty known, can be optionally in the presence of two keys ester function group or hydroxy acid functional group be reduced to any reagent of corresponding methanol.Preferred Reducing agent is the diisobutylaluminium hydride (DIBAL-H) in hexane, THF, ether, dichloromethane or its mixture.In a preferred technology, the THF solution of acrylic acid methyl ester. is cooled to about 0 ° to-78 ℃ (preferred-60 to-70 ℃), adds the DIBAL-H that is dissolved in the hexane, and the temperature of mixture is risen to room temperature.Response time can be about 2 to 24 hours.
1-propenol-3 can be known with this specialty, be converted into required pi-allyl primary amine with the technology of the hydroxyl of the primary amino radical displacement allylation of allylation.A preferred laboratory method comprises the direct formation of imino derivative, the direct formation of preferred phthalimide, and then the cracking imino group produces primary amino radical.Imino derivative can be by with suitable imines (promptly, phthalimide, butanimide, or maleimide) (for example at triaryl phosphine, triphenyl phasphine) or trialkyl phosphine and diethylazodicarboxylate exist down, in non-proton organic solvent (for example, THF Huo diox), handle and preparation easily.About 0 ° to 70 ℃ of available temperature range of reaction, about 1 to 24 hour of response time carry out.Room temperature is preferred.Imino derivative can be preferably by with hydrazine in organic solvent such as alkanol (for example, ethanol), in reflux temperature (50 ° to 100 ℃) and the reaction of about 30 minutes to 10 hours of response time and cracking.It is preferred in hydrazine processing back adding acid (for example hydrochloric acid) product being converted into acid-addition salts.Other reagent can be used to cracking imino group functional group.For example, acid imide can with the mixture heated of strong inorganic acid (for example, hydrochloric acid or sulphuric acid) or hydrochloric acid and acetic acid.Acid to alkene reaction can not be used as hydrobromic acid.End product is with conventional purification process purification and be separated into acid-addition salts easily.
Above-mentioned technology illustrates by following embodiment.
Embodiment 1
(E)-(to the fluorobenzene ethyl)-3-fluoroallylamine HCl
Steps A: 2-(tertbutyloxycarbonyl)-to the fluorophenyl ethyl n-butyrate.
Tert-butyl acetate (349ml) solution to fluorophenyl butanoic acid (25g) is handled, was at room temperature stirred 1.5 hours then with perchloric acid (1.77ml).Solution is poured in the water (350ml) that contains NaOH (48g), separated tertiary butyl ester, obtain light yellow oil by extracted with diethyl ether.With THF (200ml) the formulations prepared from solutions diisopropyl lithamide solution of diisopropylamine (22.74g) and 1.6M n-BuLi (143.7ml), be cooled to-78 ℃ and slow THF (100ml) solution that adds fluorophenyl tert-butyl acetate (26.76g).After 1 hour, THF (100ml) solution and the continuation that add ethyl chloroformate (12.19g) were at room temperature stirred 24 hours.Then mixture is poured in the water,, obtained orange (32.27g) with rare HCl aqueous solution neutralization and by the extracted with diethyl ether separated product.
Step B:2-(tertbutyloxycarbonyl)-2-(difluoromethyl)-to the fluorophenyl ethyl n-butyrate.
In THF (400ml) solution of thick 2-(tertbutyloxycarbonyl)-to fluorophenyl ethyl n-butyrate. (32.14g), add sodium tert-butoxide (19.81g).Stirred the mixture 1 hour, and be heated to 45 ℃ then, and in 15 minutes, feed ClCHF fast
2Gas.At ClCHF
2Continue in the atmosphere to stir 1 hour, make temperature reduce to room temperature.Reactant mixture is poured in water/saline solution, separated crude product, obtain orange (34.55g) by extracted with diethyl ether.
Step C:2-(to the fluorobenzene ethyl)-3-perfluoroalkyl acrylate (E)-ethyl ester
With 2-(tertbutyloxycarbonyl)-2-(difluoromethyl)-to trifluoroacetic acid (168ml) solution stirring of fluorophenyl ethyl n-butyrate. (30.28g) 1 hour, excessive trifluoroacetic acid was removed in evaporation then.Residual grease (25.82g) is dissolved in THF (230ml) and slowly handles with 2MNaOH (80ml) make pH be no more than 7.02.After adding solution, restir solution 15 minutes is extracted into product in the ether then.Evaporation ether, residue filter a short silicagel column, make solvent with 5% ethyl acetate in the petroleum ether.Evaporating solvent obtains the light orange oily product (15.75g) of substantially pure.
Step D:(E)-2-(to the fluorobenzene ethyl)-3-fluorine allyl alcohol
Hexane (350ml) solution of 2-(to the fluorobenzene ethyl)-3-perfluoroalkyl acrylate (E)-ethyl ester (15.70g) is cooled to-10 ℃, uses hexane solution (1M solution, 196ml) processing of diisobutylaluminium hydride then at leisure.At room temperature stirred 90 minutes, and be cooled to 10 ℃ again, three methanol (196ml) and 6M hydrochloric acid (245ml) are handled successively.Add entry, the extracted with diethyl ether separated product then boils off solvent, obtains almost purified alcohol (11.36g).
Step e: (E)-the adjacent diformazan acylimino of 1-fluoro-2-(being)-3-benzene propylene to fluorophenethyl
With (E)-2-(to the fluorobenzene ethyl)-3-fluorine allyl alcohol (11.36g), THF (400ml) solution of phthalimide (8.43g) and triphenyl phasphine (15.3g) is cooled to 0 ℃, uses THF (50ml) solution-treated of diethylazodicarboxylate (9.99g) at leisure.At room temperature continue excessive whipping, evaporating liquid stays an orange paste (30g) then.Separate pure products with silica gel chromatography (20% ethyl acetate in the petroleum ether is made eluant), obtain light yellow solid (13.9g).
Step F: (E)-(to the fluorobenzene ethyl)-3-fluorine allyl amine HCl
Mixture in ethanol (5ml) refluxed 2.5 hours with (E)-1-fluoro-2-(to the fluorobenzene ethyl)-3-phthaloyl imino propylene (0.26g) and hydrazine hydrate (80mg).Add 6N HCl (1.2ml) and evaporating mixture to doing.Residue is dissolved in NaOH (10ml) and separates thick amine by extracted with diethyl ether.Being dissolved in THF (10ml) also handles with two dimethyl dicarbonate butyl esters (194mg).Reflux solution 2 hours is separated thick N-Boc derivant by ether extraction then.Silica gel chromatography (25% ethyl acetate in the petroleum ether) purification obtains almost colourless oily pure material (180mg).Be dissolved in also placing in the saturated ether of HCl (12ml) and spend the night.Filtration provides title product (30mg), is colourless tablet (m.p.131 ℃).
The invention provides a kind of method for the treatment of the presenile dementia patient who needs treatment, comprise (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt to said patient's administering therapeutic effective dose.Here used predicate " patient " refers to suffer from the homoiothermic animal of presenile dementia, for example people.Term " patient who needs treatment " refers to the patient of needs treatment presenile dementia.
Presenile dementia is also referred to as presenile dementia type alzheimer disease (SDAT), is because the class senilism degenerative dementia that forehead and brain occipital bone lobar atrophy cause.Presenile dementia comprises the carrying out property forfeiture of memory, and the intellectual function decline is indifferent, language and gait disorder and disorientation.The course of disease is from taking some months to four by 5 years to completely losing intellectual function in early days.Be familiar with this professional diagnostician can determine to suffer from presenile dementia on the basis of standard diagnostics process and test patient.
In effective treatment of the present invention, patient's presenile dementia makes the forfeiture of carrying out property, the intellectual function decline, indifferent of memory with controlled, and language and gait disorder and disorientation are slowed down, interrupt, stop or stop.This treatment can't cause the elimination fully of disease or return to normal level of intelligence.
(E)-the treatment effective dose of 2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt be with single dose or multiple dose to patient's administration, the amount that makes the forfeiture of carrying out property of memory, intellectual function decline, indifferent, language and gait disorder and disorientation be slowed down, interrupt, stop or cease to have effect to control presenile dementia.
(E)-and 2-(to the fluorobenzene ethyl)-3-fluoroallylamine, or the treatment effective dose of its pharmaceutically acceptable salt can be by be familiar with this professional diagnostician by easily determining with known technology or the observed result that obtains under analogue.When determining treatment effective dose or dosage, the diagnostician need consider multiple factor, includes, but is not limited to: patient's individual size, age and general health; The order of severity of disease; Each reaction; Administering mode; The biological effectiveness characteristic of the preparation of administration; The dosage range of selecting; The use of companion's row medication; With other correlation circumstance.
(E)-the treatment effective dose of 2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt changed at about 0.001mg/Kg/ days to 1.0mg/Kg/ days.Preferred amount is desirably in variation in about 0.01mg/Kg/ days to about 0.25mg/Kg/ days.
When the patient of presenile dementia is suffered from treatment, chemical compound (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt can make any form or the method administration of chemical compound with effective dose performance biopotency, comprise oral and the parenteral route administration.For example, chemical compound can be oral, subcutaneous, administration such as muscle, intravenous, percutaneous, intranasal, rectum.Oral administration generally is preferred.Percutaneous dosing also is preferred.The professional who is familiar with the preparation preparation can be easily according to the concrete feature of selected compounds, sick selected suitable form of medication and the mode of relevant situation with other of stage.
Chemical compound can be separately or with pharmaceutically acceptable carrier or the bonded pharmaceutical compositions administration of excipient, its ratio and character are by the pharmacy practice decision of dissolubility and chemical property, selected route of administration and the standard of selected compounds.Chemical compound of the present invention (they self are effective) will be with their pharmaceutically-acceptable acid addition form preparation and administration, in order that its stability, be convenient to crystallization, increase dissolubility etc.
Pharmaceutical composition prepares in the known mode of pharmacy.Carrier or excipient can be can be as the carrier of active ingredient or solid, semisolid or the fluent material of medium.Suitable carriers or excipient are that this specialty is known.Pharmaceutical composition can be suitable for oral or non-intestinal to be used, and can tablet, capsule, suppository, solution, suspending agent, plaster etc. are to patient's administration.
Chemical compound of the present invention can be taken orally, for example, and the carrier administration that maybe can eat with inert diluent.They can wrap in the capsule or be pressed into tablet.Be the purpose of oral therapeutic administration, chemical compound can be impregnated in the excipient and with forms such as tablet, lozenge, capsule, ingredients, suspending agent, syrup, bag medicine wafer paper, chewing gum and use.These preparations contain at least 0.1% The compounds of this invention (active component), and can change with concrete form, generally 0.5% between about 20% Unit Weight.The amount of this chemical compound is the amount that can obtain suitable dose in the compositions.Preferred compositions of the present invention and preparation are made into oral dosage unit form and contain 0.05-25 milligrams The compounds of this invention.
Tablet, pill, capsule, lozenge etc. also can contain one or more following adjuvants: binding agent such as microcrystalline Cellulose, Tragacanth or gelatin; Excipient such as starch or lactose, disintegrating agent such as alginic acid, Primogel
TM, cereal starch etc.; Lubricant such as magnesium stearate or Sterotex
TMAntiseize paste such as colloidal silica; Can be added into sweeting agent such as sucrose or glucide, or flavoring agent such as Herba Menthae, methyl salicylate or the agent of orange flavor.When dosage unit form is capsule, except that the material of the above-mentioned type, also contain liquid-carrier such as Polyethylene Glycol or fatty oil.Other dosage unit form can contain other various materials that improve the dosage unit physical form, for example, and as coating.Like this, tablet or pill can be used sugar, lac or other casing agent coating.Except that The compounds of this invention, syrup can contain sucrose and make sweeting agent and some antiseptic, dyes and dyestuffs and flavoring agent.The material that is used to prepare this multiple compositions should be that pharmacy is pure and nontoxic in use amount.
Be the purpose of non-intestinal treatment administration such as muscle, intravenous and subcutaneous administration, chemical compound of the present invention can mix in solution or the suspending agent.These preparations can contain at least 0.01% The compounds of this invention, but the weight change between 0.01 and about 50%.The amount that is present in the The compounds of this invention in this based composition is the amount that can obtain suitable dose.Preferred compositions of the present invention and preparation are made into non-intestinal dosage unit and contain 0.01 to 10 milligram of The compounds of this invention.
Solution or suspending agent also can comprise one or more following adjuvants: sterile diluent such as water for injection, saline solution, fixing oil, Polyethylene Glycol, glycerol, propylene glycol or other synthetic; Antibacterial such as benzylalcohol or methyl paraben; Antioxidant such as ascorbic acid or sodium sulfite; Chelating such as ethylene diaminetetraacetic acid; Buffer agent such as acetate, citrate or phosphate and be used to regulate medicament such as the sodium chloride or the glucose of intensity.Parenteral formulation can be contained in the ampoule, in the multiple dose vials that syringe that can at will use or glass or plastics are done.
But chemical compound of the present invention is topical also.This can finish by the solution for preparing chemical compound to be administered simply, preferably when being with or without other excipient with solvent such as the ethanol or the dimethyl sulfoxine (DMSO) of known promotion skin absorbs.Preferred topical is to use plaster.
The factor that will consider when using plaster is that this specialty is known and comprise: the optimum level that need obtain the pharmaceutically active compound that required treatment replys, by the physics of the transmission system material of required application decision and the inherence restriction of chemical property aspect, the Kinetics and Mechanism that pharmaceutical active compounds transmits from transmission system, the mechanism and the speed of removing pharmaceutical active compounds from the patient.
Usually, plaster is chemical compound to be administered and excipient, and normally a kind of combination of polymeric material is intended to make pharmaceutical active compounds speed transmission with control in the specific time.The thin slice that the instrument that plaster is contacted with skin or mucosa by bottom, the reservoir that contains chemical compound, adhesion coating or maintenance plaster is formed.
Suitably selecting bottom is that this specialty is known and familiar.Bottom generally is not see through chemical compound, thereby limits the one side of plaster.
Reservoir is the part that contains chemical compound in the plaster, comprises the very wide class formation that can finish this function.Reservoir can be the band wall container that contains liquid, solid, suspension, solution state chemical compound, or in polymeric substrate.Chemical compound can be contained in or flow or control in the substrate of transfer rate by diffusion by microporosity.Reservoir can be formed by containing the microcapsule that is dispersed throughout the chemical compound in solid or the microporosity substrate in a large number.Reservoir can be made up of the chemical compound that is adsorbed on the polymeric matrix.Reservoir can be formed or be had permeable material in the one side of reservoir and allow chemical compound to pass through by permeable material.Reservoir can adopt chemical compound to be released the form that control material surrounds, as being encased by encapsulate, layer or container.
Plaster can have permeable membrane, the transfer rate of its decision chemical compound, and this class film is known and familiar in this specialty.Film can flow, see through the diffusion of film or control the transmission of chemical compound by the VISCOUS FLOW of pressure inducement by microporosity.
The example of plaster is at U.S. Patent number 3,742, narration in 951,3,797,494,3,996,934 and 4,031,894.These plaster generally contain the bottom that limits its one side surface, and the permeable adhesion coating of chemical compound limits the surface of another side, is inserted with a reservoir that contains chemical compound between two surfaces at least.In addition, chemical compound can be contained in the large quantity of micro-capsule that is dispersed throughout in the permeable adhesion coating.Chemical compound from reservoir or microcapsule by or the continuous transmission of symphysis that directly contact with receiver's skin or mucosa, or be delivered to the activating agent that contacts with receiver's skin or mucosa can be through in the adhesion coating.Under the situation of microcapsule, coating agent is also as film.If activating agent is by skin absorbs, in check and predetermined activating agent mobile is administered into the receiver.
Do not need the example of the plaster of film to be described in US-3,921, in 636, and comprise the pharmaceutical active compounds that is contained in the support matrix, chemical compound from substrate with gradually, the constant and in check speed transmission of needs.The release of at least two classes is possible in this system.Support matrix is permeable for chemical compound by diffusion or the mobile release of microporosity.Release is speed controlling.When occurring in the substrate atresia by the release of spreading.The pharmacy compounds effective is dissolved in and spreads all over support matrix itself.Occur in the pharmacy compounds effective when liquid phase is transferred in the hole of support matrix by the mobile release of microporosity.The speed controlling that discharges is administered to the amount of patient's chemical compound.
The following example represents to be used for administration (E)-(to the preparation of the plaster of fluorobenzene ethyl-3-fluoroallylamine.These embodiment are understood that only to illustrate, and do not limit the scope of the invention in all senses.Used following term has indicated meaning among these embodiment: " g " refers to gram, and " μ g " refers to microgram, and " mmol " refers to mM, " ml " refers to milliliter, " ℃ " refer to degree centigrade that " HPLC " refers to high performance liquid chromatography, " μ L " refers to that microlitre, " cm " refer to centimetre, " cm
2" refer to square centimeter, " mm " refers to millimeter, and " M " refers to molar concentration, and " nm " refers to nanometer, and " hr " refers to hour.
Embodiment 2
(E)-(to the fluorobenzene ethyl)-3-fluoroallylamine
Mix (E)-(to the fluorobenzene ethyl)-3-fluoroallylamine HCl (26.5g, 0.113mmol) and water.Make solution be alkalescence and use hexane extraction with sodium hydroxide.Merge organic layer, MgSO
4Drying is filtered, and vacuum evaporation obtains 22.38g oily title compound.
1HNMR(CDCl
3)δ1.20(s，2H)，2.45(m，2H)，2.73(m，2H)，3.13(m，2H)，6.55(d，J＝80.0，1H)，6.97(m，2H)，7.16(m，2H)；
13C?NMR(CDCl
3)δ161.31(d，J
C，F＝24?3.2)，145.36(d，J
C，F＝255.2)，137.15(d，J
C，F＝2.8)，129.6?5(d，J
C，F＝8.3)，1?23.50(d，J
C，F＝3.7)，115.01(d，J
C，F＝20.4)，41.58(d，J
C，F＝9.2)，33.40(d，J
C，F＝2.8)，26.83(d，J
C，F＝3.7).
Embodiment 3
Preparation contains the plaster of (E)-(to the fluorobenzene ethyl)-3-fluoroallylamine
Merge (E)-(to the fluorobenzene ethyl)-3-fluoroallylamine and substrate, NationalStarch Duro-Tak 1074; 10%, 20%, 30%, 40% and 50% (W/W) forms medicine/substrate.Behind medicine dissolution, medicine/substrate is coated on a slice polyethylene with Lab Hand Coater.With the sheet that applies 50 ℃ of dryings 15 minutes in stove.Put bottom on the upper strata of medicine/adhesion coating and remove bubble and obtain thin slice, can cut out from it and contain 10%, 20%, the plaster of 30%, 40% and 50 (W/W, medicine/substrate) with cylinder.
Embodiment 4
(E)-skin permeation study of (to the fluorobenzene ethyl)-3-fluoroallylamine
(E)-dermal osmosis of (to the fluorobenzene ethyl)-3-fluoroallylamine spreads cell (FDC-400 type by Franz, Grown Glass Co.) makes dissolve medium with nude mouse skin, water (pH=7.0), according to M.Mahjour etc., J.of Controrolled Release 14,243-252, (1990) method is carried out under 37 ℃.Nude mouse skin is obtained from six all big nude mouses (Charles River Co.), and cell adapted with diffusion.The epidermis side of skin is put the saturated aqueous solution of 100 μ L, 150 μ L and 200 μ L (E)-(to the fluorobenzene ethyl)-3-fluoroallylamine.(E)-the saturated aqueous solution density of (to the fluorobenzene ethyl)-3-fluoroallylamine is 1.124g/ml.Drug level in the dissolve medium, was measured 4,8 with HPLC in 12,24 and 28 hours.HPLC carries out in Waters 845 systems that have Waters WISP 712 automatic injectors, Waters 600E pump and Waters 486 UV detectors.With DuPont Zor-bax Rx C8 post, 4.6mm * 25cm, the 78% 0.05M sodium phosphate and 22% acetonitrile that are adjusted to pH2.9 with phosphoric acid are made eluant.Flow velocity is the 1.5ml/ branch, detects at 265nm.
Table 1 has been summarized the skin permeation study result of (E)-(to the fluorobenzene ethyl)-3-fluoroallylamine.
| Time (hr) | Drug osmotic (μ g/cm at 100 μ L 2) | Drug osmotic (μ g/cm at 150 μ L 2) | Drug osmotic (μ g/cm at 200 μ L 2) | ||||||
| Sample 1 | Sample 2 | Sample 3 | Sample 1 | Sample 2 | Sample 3 | Sample 1 | Sample 2 | Sample 3 | |
| ?????4 | ?4798.10 | ??4592.82 | ??4508.32 | ??6391.68 | ??5464.09 | ??4582.53 | ??6234.36 | ??6256.11 | ?5723.97 |
| ?????8 | ?9626.69 | ??8763.95 | ??8688.90 | ??10014.32 | ??9400.18 | ??8276.54 | ??10874.62 | ??11033.97 | ?10298.52 |
| ?????12 | ?14828.55 | ??13221.46 | ??12931.25 | ??15103.49 | ??13509.45 | ??12146.41 | ??15447.40 | ??15865.07 | ?14819.10 |
| ?????24 | ?24613.43 | ??21888.35 | ??21243.21 | ??25527.66 | ??21762.32 | ??20271.37 | ??24634.65 | ??25613.63 | ?23934.88 |
| ?????28 | ?29029.84 | ??25982.51 | ??24795.02 | ??30164.52 | ??25183.02 | ??23683.37 | ??28760.30 | ??30068.48 | ?27996.68 |
| Dermal osmosis speed (ug/cm 2/hr) | ??974.06 | ??859.01 | ??815.96 | ??976.51 | ??796.97 | ??773.67 | ??903.37 | ??956.15 | ?893.90 |
| Meansigma methods ± standard deviation (μ g/cm 2/hr) | ????????????883.01±81.74 | ???????????849.05±111.00 | ????????????917.81±33.54 | ||||||
Embodiment 5
Contain (E)-skin permeation study of the plaster of (to the fluorobenzene ethyl)-3-fluoroallylamine
According to M.Mahjour etc., J.of Controlled Release 14,243-252, the method for (1990), contain 10%, 20%, 30%, 40% and 50% (W/W, medicine/substrate) (E)-skin permeation study of the plaster of (to the fluorobenzene ethyl)-3-fluoroallylamine spreads cell (FDC-400 type by Franz, Grown Glass CO.) use nude mouse skin, water (PH=7.0) carries out under 37 ℃ as dissolve medium.Nude mouse skin is obtained from six all big nude mouses (Charles River CO.), and adapts to the diffusion cell.The plaster of (W/W, (E)-(to the fluorobenzene ethyl)-3-fluoroallylamine/substrate) is used to the epidermis side of skin to contain 10%, 20%, 30%, 40% and 50%.The concentration of dissolve medium Chinese medicine is measured by top embodiment 4 said HPLC, and measures infiltration rate.The result is summarized in the table 2.
Table 2
| Medicine/substrate (w/w) | Dermal osmosis speed ± standard deviation (μ g/cm 2/hr) |
| ?????10％ | ????????7.60±0.87 |
| ?????20％ | ????????36.73±2.11 |
| ?????30％ | ????????96.78±8.55 |
| ?????40％ | ???????181.16±10.35 |
| ?????50％ | ???????249.16±15.04 |
Claims (14)
1. a method of giving the patient treatment presenile dementia that needs treatment comprises (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically-acceptable acid addition to said patient's administering therapeutic effective dose, and wherein plaster is passed through in administration.
2. according to the process of claim 1 wherein that pharmaceutically-acceptable acid addition is selected from hydrochloric acid, hydrobromic acid, sulfonic acid, sulphuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, 4,4 ＇-di-2-ethylhexylphosphine oxide (3-hydroxyl-2-naphthoic acid), succinic acid, methanesulfonic acid, acetic acid, propanoic acid, tartaric acid, citric acid, lactic acid, malic acid, the Alpha-hydroxy phenylacetic acid, cinnamic acid, Palmic acid, the salt of itaconic acid and benzenesulfonic acid.
3. according to the method for claim 2, wherein chemical compound is (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine hydrochlorate.
4. according to the process of claim 1 wherein that chemical compound is (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine.
5. according to the process of claim 1 wherein that the treatment effective dose of (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically-acceptable acid addition is about 0.001mg/kg/ days to about 1.0mg/kg/ days.
6. according to the method for claim 5, wherein the treatment effective dose of (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its acid-addition salts of pharmaceutically accepting is about 0.01mg/kg/ days to about 0.25mg/kg/ days.
7. according to the process of claim 1 wherein that plaster comprises support matrix and bottom.
8. according to the process of claim 1 wherein that plaster comprises bottom, permeable layer and reservoir.
9. plaster comprises support matrix, bottom and (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt.
10. according to the plaster of claim 9, wherein pharmaceutically-acceptable acid addition is selected from hydrochloric acid, hydrobromic acid, sulfonic acid, sulphuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, 4,4 ＇-di-2-ethylhexylphosphine oxide (3-hydroxyl-2-naphthoic acid), succinic acid, methanesulfonic acid, acetic acid, propanoic acid, tartaric acid, citric acid, lactic acid, malic acid, the Alpha-hydroxy phenylacetic acid, cinnamic acid, Palmic acid, the salt of itaconic acid and benzenesulfonic acid.
11. the plaster according to claim 10 comprises (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine hydrochlorate.
12. a plaster comprises bottom, permeable layer, reservoir and (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine or its pharmaceutically acceptable salt.
13. according to the plaster of claim 12, wherein salt is selected from hydrochloric acid, hydrobromic acid, sulfonic acid, sulphuric acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, 4,4 ＇-di-2-ethylhexylphosphine oxide (3-hydroxyl-2-naphthoic acid), succinic acid, methanesulfonic acid, acetic acid, propanoic acid, tartaric acid, citric acid, lactic acid, malic acid, the Alpha-hydroxy phenylacetic acid, cinnamic acid, Palmic acid, the salt of itaconic acid and benzenesulfonic acid.
14. according to the plaster of claim 13, wherein salt is (E)-2-(to the fluorobenzene ethyl)-3-fluoroallylamine hydrochlorate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12719093A | 1993-09-24 | 1993-09-24 | |
| US08/127,190 | 1993-09-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1131390A true CN1131390A (en) | 1996-09-18 |
Family
ID=22428772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94193473A Pending CN1131390A (en) | 1993-09-24 | 1994-08-23 | Plaster containing (E)-2-(P-fluorophenethyl)-3-fluoroallylamine for treatment of alzheimer's disease |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0720475A1 (en) |
| JP (1) | JPH09505276A (en) |
| CN (1) | CN1131390A (en) |
| AU (1) | AU684545B2 (en) |
| CA (1) | CA2172605A1 (en) |
| HU (1) | HUT75877A (en) |
| IL (1) | IL111017A0 (en) |
| NO (1) | NO961180L (en) |
| WO (1) | WO1995008325A1 (en) |
| ZA (1) | ZA947262B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100479405B1 (en) * | 2002-05-24 | 2005-03-30 | 주식회사 싸이제닉 | Cinnamic acid dimers, their preparation and the use thereof for treating neurodegenerative disease |
| WO2010033045A1 (en) * | 2008-09-16 | 2010-03-25 | Igor Anatolievich Pomytkin | Compositions and methods for prevention or treatment of beta amyloid deposition |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4861800A (en) * | 1987-08-18 | 1989-08-29 | Buyske Donald A | Method for administering the drug deprenyl so as to minimize the danger of side effects |
| JPH07507299A (en) * | 1992-05-27 | 1995-08-10 | メレルダウファーマスーティカルズ インコーポレイテッド | Use of (E)-2-(p-fluorophenethyl)-3-fluoroallylamine in the treatment of Alzheimer's disease |
-
1994
- 1994-08-23 JP JP7509764A patent/JPH09505276A/en active Pending
- 1994-08-23 HU HU9600725A patent/HUT75877A/en unknown
- 1994-08-23 CA CA002172605A patent/CA2172605A1/en not_active Abandoned
- 1994-08-23 AU AU76364/94A patent/AU684545B2/en not_active Ceased
- 1994-08-23 CN CN94193473A patent/CN1131390A/en active Pending
- 1994-08-23 EP EP94926566A patent/EP0720475A1/en not_active Withdrawn
- 1994-08-23 WO PCT/US1994/009517 patent/WO1995008325A1/en not_active Application Discontinuation
- 1994-09-19 ZA ZA947262A patent/ZA947262B/en unknown
- 1994-09-21 IL IL11101794A patent/IL111017A0/en unknown
-
1996
- 1996-03-22 NO NO961180A patent/NO961180L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU684545B2 (en) | 1997-12-18 |
| NO961180D0 (en) | 1996-03-22 |
| CA2172605A1 (en) | 1995-03-30 |
| HU9600725D0 (en) | 1996-05-28 |
| EP0720475A1 (en) | 1996-07-10 |
| WO1995008325A1 (en) | 1995-03-30 |
| JPH09505276A (en) | 1997-05-27 |
| HUT75877A (en) | 1997-05-28 |
| IL111017A0 (en) | 1994-11-28 |
| AU7636494A (en) | 1995-04-10 |
| NO961180L (en) | 1996-03-22 |
| ZA947262B (en) | 1995-05-23 |
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